practice parameter: evaluation of the child with microcephaly (an evidence-based review)

8/16/2019 Practice Parameter: Evaluation of the child with microcephaly (an evidence-based review)

1/13

Practice Parameter: Evaluation of the child withmicrocephaly (an evidence-based review)Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society

Stephen Ashwal, MD

David Michelson, MD

Lauren Plawner, MD

William B. Dobyns, MD

ABSTRACT

Objective: To make evidence-based recommendations concerning the evaluation of the child with

microcephaly.

Methods: Relevant literature was reviewed, abstracted, and classified. Recommendations were

based on a 4-tiered scheme of evidence classification.

Results: Microcephaly is an important neurologic sign but there is nonuniformity in its definition

and evaluation. Microcephaly may result from any insult that disturbs early brain growth and can

be seen in association with hundreds of genetic syndromes. Annually, approximately 25,000

infants in the United States will be diagnosed with microcephaly (head circumference 2 SD).

Few data are available to inform evidence-based recommendations regarding diagnostic testing.

The yield of neuroimaging ranges from 43% to 80%. Genetic etiologies have been reported in

15.5% to 53.3%. The prevalence of metabolic disorders is unknown but is estimated to be 1%.

Children with severe microcephaly (head circumference3 SD) are more likely (80%) to have

imaging abnormalities and more severe developmental impairments than those with milder micro-

cephaly (2 to 3 SD; 40%). Coexistent conditions include epilepsy (40%), cerebral palsy

(20%), mental retardation (50%), and ophthalmologic disorders (20% to 50%).

Recommendations: Neuroimaging may be considered useful in identifying structural causes in the

evaluation of the child with microcephaly (Level C). Targeted and specific genetic testing may be

considered in the evaluation of the child with microcephaly who has clinical or imaging abnormali-

ties that suggest a specific diagnosis or who shows no evidence of an acquired or environmental

etiology (Level C). Screening for coexistent conditions such as cerebral palsy, epilepsy, and sen-

sory deficits may also be considered (Level C). Further study is needed regarding the yield of

diagnostic testing in children with microcephaly. Neurology ® 2009;73:887–897

GLOSSARY CP cerebral palsy; GDD global developmental delay; HC head circumference; MRE medically refractory epilepsy;OMIM Online Mendelian Inheritance in Man.

Microcephaly is an important neurologic sign but

there is nonuniformity in the definition of micro-

cephaly and inconsistency in the evaluation of af-

fected children.1,2 Microcephaly is usually defined as

a head circumference (HC) more than 2 SDs below

the mean for age and gender.2,3 Some academics have

advocated for defining severe microcephaly as an HC

more than 3 SDs below the mean.4-7 Other than

where specified, this parameter uses the usual defini-

tion of microcephaly. Recommended methods for

HC measurement are described in appendix 2.

If HC is normally distributed, 2.3% of children

should by definition be microcephalic. However,

published estimates for HC 2 SD at birth are far

lower, at 0.56%8 and 0.54%.9 The difference may be

accounted for by a non-normal distribution, postna-

tal development of microcephaly, or incomplete as-

certainment. Severe microcephaly would be expected

Supplemental dataatwww.neurology.org

From the Division of Child Neurology (S.A., D.M.), Department of Pediatrics, Loma Linda University School of Medicine, CA; Division of Pediatric

Neurology (L.P.), Children’s Hospital Regional Medical Center, Seattle, WA; and The University of Chicago (W.D.), Department of Human

Genetics, IL.

Appendices e-1 through e-6 and references e1– e12 are available on t he Neurology Web site at www.neurology.org.

Approved by the Quality Standards Subcommittee on November 5, 2008; by the Child Neurology Society (CNS) Practice Committee on August 2,

2009; by the AAN Practice Committee on November 20, 2008; and by the AAN Board of Directors on July 7, 2009.

Disclosure: Author disclosures are provided at the end of the article.

Address correspondence and

reprint requests to the American

Academy of Neurology, 1080

Montreal Avenue, St. Paul, MN

55116

[email protected]

SPECIAL ARTICLE

Copyright © 2009 by AAN Enterprises, Inc. 887


2/13

in 0.1% of children if normal distribution is as-

sumed, which agrees with the published estimate of

0.14% of neonates.9

Microcephaly may be described as syndromic or

as pure, primary, or true (microcephalia vera), de-

pending on the presence or absence of extracranial

malformations or dysmorphic facial features. These

terms do not imply a distinct etiology and can be

seen with either genetic or environmental causes of

neurodevelopmental impairment. Some of the more

common causes are outlined in table 1.

A comprehensive history, growth records for the

child and close relatives, and a detailed physical ex-

amination will often suggest a diagnosis or direction

for further testing. Advances in neuroimaging and

genetics have improved understanding of the causes

of microcephaly, suggesting new approaches to classi-

fication and testing. In developing diagnostic algo-

rithms for microcephaly defined as congenital or of

postnatal onset, we also examined whether the diagnos-

tic yield depended on the severity of microcephaly.

DESCRIPTION OF THE ANALYTIC PROCESS

Literature examined for this parameter (1966–

2007) included 4,500 titles and abstracts, of which

150 articles were selected for review. See appendices

e-1A–e-1C on the Neurology ® Web site at www.

neurology.org for information on databases, search

terms, and article classification.

ANALYSIS OF EVIDENCE What is the role of diag-

nostic testing of children with microcephaly? Neuroimaging.

CT data are available from 2 Class III studies involv-ing 143 children with microcephaly (table e-1).10,11

In one study, 61% of 85 children with microcephaly

(2 SD) had abnormal CT findings.10 Patients

with a known history of perinatal or postnatal brain

injury (n 22) had the highest percentage of imag-

ing abnormalities (91%). Patients with one or more

extracranial congenital anomalies (n 30) had an

intermediate yield (67%). The lowest yield (36%)

was in patients (n 33) with no evidence by history

or examination of a brain injury, although 4 patients

had major CNS malformations that were not sus-

pected clinically. Imaging findings were classifiedinto 4 groups: normal (39%), mild atrophy/ventricu-

lar dilatation (31%), moderate to severe atrophy/

ventricular dilatation (28%), and isolated parenchymal

abnormalities (2%). The degree of microcephaly corre-

lated with the severity of cerebral atrophy or ventricular

dilatation. Five cases (6%) had findings that led to a

more specific diagnosis (e.g., schizencephaly, holo-

prosencephaly). In a second study of 58 children with

microcephaly (HC 2 SD), head size did not corre-

late with CT findings, but there were correlations be-

tween CT findings and mental retardation, motor

disturbance, and epilepsy.11 CT was felt to be useful for

determining prognosis.

Data from 2 Class III MRI studies of 88 children

with microcephaly found abnormalities in 67% and

80% (table e-1).12,13 In one study, abnormalities were

detected in 68% of children in whom a genetic disor-

der was suspected or diagnosed, with the most fre-

quent findings being neuronal migrational disorders

or callosal malformations.13 In the children with

postnatal onset microcephaly, 100% showed abnor-

malities, with hydranencephaly and infarction being

most common. The second studyclassified MRI abnor-

malities into 4 groups: congenital cytomegalovirus

(CMV) infection (n 6), cerebral malformations/

myelination disorders (n 16), unclassifiable patho-

logic findings (n 8), and normal (n 3).12 The high

prevalence of CMV infection was due to case selection

bias. In this small study, the authors did not find a cor-

relation between the severity of the cerebral malforma-

tion and neurodevelopmental disturbances.

Two Class III studies examined the diagnostic yieldof either CT or MRI and the severity of microcephaly

(table e-1).14,15 In one study, children with mild micro-

cephaly (2 SD) had a yield of 68.8% whereas those

with severe microcephaly (3 SD) had a yield of

75%. A second study also found that children with se-

vere microcephaly were more likely to have imaging ab-

normalities (80%) than those with mild (2 to 3

SD) microcephaly (43%).15 There was correlation be-

tween imaging findings and neurodevelopmental out-

comes as measured by the Bayley Scales of Infant

Development or the McCarthy Scales of Children’s

Abilities, depending on the patient’s age.15 Develop-

mental quotients in the normal imaging group were 70

or greater, whereas quotients in the abnormal imaging

group were 52 or less.

Conclusions. Data from 6 Class III studies (2 CT, 2

MRI, 2 CT/MRI) of 292 children with microceph-

aly found diagnostic yields ranging from 43% to

80%. In 2 studies, children with severe microcephaly

(3 SD) were more likely (i.e., 75%, 80%) to have

an abnormal MRI than those with milder micro-

cephaly. MRI detected brain abnormalities typically

beyond the sensitivity of CT.Recommendation. Neuroimaging may be considered

useful in identifying structural causes in the evaluation

of the child with microcephaly (Level C).

Clinical context. MRI often reveals findings that

are more difficult to visualize on CT, such as migra-

tional disorders, callosal malformations, structural

abnormalities in the posterior fossa, and disorders of

myelination, and is considered the superior diagnos-

tic test.16 An MRI-based classification scheme of mi-

crocephaly is outlined in appendix 3.17 While based

on retrospective review, its usefulness is apparent as

888 Neurology 73 September 15, 2009


3/13

certain malformations (e.g., lissencephaly, schizen-

cephaly) are well known to be associated with severe

neurologic impairment and specific gene abnormali-

ties have been found in several of these disorders.

Thus, MRI is often helpful for definitive diagnosis,

prognosis, and genetic counseling.

Genetic testing. There are very few data as to the

prevalence and specific type of genetic abnormali-

ties in children with microcephaly. In one Class II

study of 58 children referred for evaluation of mi-

crocephaly, 9 (15.5%) were found to have a ge-

netic etiology.18 One patient had Angelman

syndrome, 1 had tuberous sclerosis, 2 had multiple

congenital anomalies, and 5 had a family history

of microcephaly. A Class III study of 30 infants in

whom prenatal microcephaly was diagnosed by ul-

trasound found associations with a chromosome

disorder in 23.3%, multiple congenital anomalies

in 23.3%, and specific genetic syndromes in

20%.19 In this cohort, an additional 16.7% had

holoprosencephaly, a malformation often associ-ated with genetic abnormalities.19

Conclusions. Genetic etiologies may be found in

15.5% (Class II, n 58) to 53.3% (Class III, n

30) of children with microcephaly. MRI studies may

detect specific malformations associated with well-

described genetic conditions.

Recommendation. Specific targeted genetic testing

may be considered in the evaluation of the child with

microcephaly in order to determine a specific etiol-

ogy (Level C).

Clinical context. Microcephaly has been associated

with numerous genetic etiologies (appendix 4), in-

cluding syndromes whose causes are as yet unidenti-

fied but which may be elucidated by further

research.20 Because the genetics of microcephaly is a

rapidly evolving field, currently available data likely

underestimate the importance and relevance of ge-

netic testing as part of the diagnostic evaluation of

children with microcephaly.20 Many of the micro-

cephaly genes identified to date have been associated

with specific phenotypes, allowing more targeted

clinical testing. Available screening tests for chromo-

somal deletions and duplications include karyotyp-ing, subtelomeric fluorescent in situ hybridization, and

bacterial artificial chromosome or oligo-based compara-

tive genomic hybridization.2,20,21 As the diagnostic

yields of these tests in children with microcephaly is

currently unknown, specific recommendations regard-

ing their use cannot be made at this time.

Metabolic testing. Metabolic disorders rarely present

with nonsyndromic congenital microcephaly, with 3

notable exceptions: maternal phenylketonuria, in which

the fetal brain is exposed to toxic levels of phenylala-

nine; phosphoglycerate dehydrogenase deficiency, a dis-

Table 1 Etiologiesof congenitaland postnatal onset microcephaly

Congenital Postnatal onset

Genetic Genetic

Isolated Inborn errors of metabolism

Autosomal recessive microcephaly Congenitaldisorders ofglycosylation

Autosomal dominantmicrocephaly Mitochondrial disorders

X-linked m icrocephaly Peroxisomal d isorders

Chromosomal (rare: “apparently” balanced rearrangementsand ringchromosomes)

Menkes disease

Amino acidopathies and organic acidurias

Glucose transporter defect

Syndromic Syndromic

Chromosomal

Trisomy 21,13, 18

Unbalanced rearrangements

Contiguous g ene d eletion Contiguous g ene d eletion

4pdeletion(Wolf-Hirschhornsyndrome) 17p13.3 deletion (Miller-Diekersyndrome)

5p deletion (cri-du-chat syndrome)

7q11.23 deletion (Williams syndrome)

22q11 deletion (velocardiofacialsyndrome)

Single gene defects Single gene defects

Cornelia d e Lange s yndrome Rett s yndrome

Holoprosencephaly (isolated orsyndromic)

Nijmegen breakage syndrome

Smith-Lemli-Opitz syndrome Ataxia-telangiectasia

Seckel syndrome Cockayne syndrome

Aicardi-Goutieres syndrome

XLAGsyndrome

CohensyndromeAcquired Acquired

Disruptive injuries Disruptive injuries

Death o f a monozygous t win Traumatic b rain i njury

Ischemic stroke Hypoxic-ischemic encephalopathy

Hemorrhagic s troke Hemorrhagic a nd i schemic s troke

Infections Infections

TORCHES (toxoplasmosis,rubella,cytomegalovirus,herpes simplex,syphilis) and HIV

Meningitis and encephalitis

Congenital HIV encephalopathy

Teratogens Toxins

Alcohol , hydantoin, r adi ation Lead p oi soning

Maternal p henylketonuri a Chroni c renal f ailure

Poorly controlled maternal diabetes

Deprivation Deprivation

Maternal h ypothyroidism Hypothyroidism

Maternal folate deficiency Anemia

Maternal malnutrition Malnutrition

Placental i nsufficiency Congenital h eart d isease

Reprinted with permission from Elsevier from: Abuelo D. Microcephaly syndromes. Semin

Pediatr Neurol 2007;14:118–127. Note that there are approximately 500 listings for mi-

crocephaly in OMIM (http://www.ncbi.nlm.nih.gov/omim).

Neurology 73 September 15, 2009 889


4/13

order of L-serine biosynthesis; and Amish lethal

microcephaly, which is associated with 2-ketoglutaricaciduria.22 Metabolic disorders associated with syn-

dromic congenital microcephaly are listed in appendix

e-2. Metabolic disorders are more likelyto cause postna-

tal onset microcephaly and are typically associated with

global developmental delay (GDD). As was published

in a practice parameter on the topic, the diagnostic yield

of routine screening for inborn errors of metabolism in

children with GDD is about 1% and the yield may

increase to 5% in specific situations, such as when mi-

crocephaly is present.23

Conclusions. The prevalence of metabolic disorders

among children with microcephaly is unknown.Based on prior analysis of studies of children with

GDD, it is likely 1% to 5%.

Recommendation. There is insufficient evidence to

support or refute obtaining metabolic testing on a

routine basis for the evaluation of the newborn or

infant with microcephaly (Level U).

Clinical context. Microcephaly is common in GDD

and the yield of metabolic testing may be higher when

the following are present: a parental history of consan-

guinity, a family history of similar symptoms in rela-

tives, episodic symptoms (seizures, ataxia, vomiting,

encephalopathy), developmental regression, extracra-

nial organ failure, or specific findings on neuroimag-

ing.23 Metabolic testing may also have a higher yield in

children whose microcephaly remains unexplained after

other evaluations have been done. There are insufficient

data to recommend when and how metabolic testing

should be done, although it is reasonable to test infants

with severe primary congenital microcephaly for the el-

evated urine alpha-ketoglutaric acid found in Amish le-

thal microcephaly.23

What neuro logic disorders are associated with micro-

cephaly? Epilepsy. Data from one Class III study involv-

ing 66 children with microcephaly (2 SD) found

an overall prevalence of epilepsy of 40.9%.24 Two Class

III studies suggest that epilepsy is more common in

postnatal onset than in congenital microcephaly. In one

study, epilepsy occurred in 50% of children with post-

natal onset microcephaly compared to only 35.7% of

those withcongenital microcephaly.24 The second study

found that epilepsy was 4 times more common in post-

natal onset microcephaly.25

Microcephaly is a significant risk factor for medi-

cally refractory epilepsy (MRE).26-28 In a Class III

study of 30 children, microcephaly was found in

58% of those with MRE compared to 2% in whom

seizures were controlled (odds ratio 67.67; p

0.001).27

Epilepsy is a prominent feature of some types of

syndromic microcephaly, which are summarized

in table 2. Studies have not examined the role of

obtaining a routine EEG in children with micro-

cephaly. In one Class III study of children with

microcephaly, EEG abnormalities were found in

51% of 39 children who either had no seizures or

had occasional febrile seizures.24 Epileptiform

EEG abnormalities were present in 78% of 18

children with MRE.

Conclusions. Children with microcephaly are more

likely to have epilepsy, particularly epilepsy that is diffi-

cult to treat. Certain microcephaly syndromes are asso-

ciated with a much higher prevalence of epilepsy. There

are no systematic studies regarding EEG testing of chil-

dren with microcephaly with and without epilepsy.

Recommendations.

1. Because children with microcephaly are at risk for

epilepsy, physicians may consider educating caregiv-

ers of children with microcephaly on how to recog-

nize clinical seizures (Level C).

2. There are insufficient data to support or refute

obtaining a routine EEG in a child with micro-

cephaly (Level U).

Cerebral palsy. Data from a Class II study of chil-

dren with developmental disabilities found cerebral

palsy (CP) in 21.4% of the 216 children with micro-

Table 2 Severeepilepsy and microcephaly associated genetic syndromes

Disorder Gene(s)

Structural malformations

Classic lissencephaly (isolatedLIS sequence) Lis1, DCX, TUBA1A

Lissencephaly: X-linked withabnormalgenitalia

ARX

Lissencephaly: autosomal recessive withcerebellar hypoplasia

RELN

Bilateralfrontoparietalpolymicrogyria(COB) GPR56

Periventricular heterotopia with microcephaly ARFGEF2

Schizencephaly EMX2 (rare)

Holoprosencephaly H PE1 21q22 .3 HPE 6 2 q3 7.1

HPE2 2p21 HPE7 9q22.3

HPE3 7q36 HPE 8 14q13

H PE4 18p11 .3 HPE9 2 q14

HPE513q32

Syndromes

Wolf-Hirschhorn syndrome 4p

Angelman syndrome UBE3A,15q11-q13

Rettsyndrome Xp22,Xq28

MEHMO(mental retardation, epilepsy,hypogonadism, microcephaly, obesity)

Xp22.13-p21.1

Mowat-Wilson syndrome (microcephaly,mental retardation, distinct facial featureswith/without Hirschsprung disease)

ZFHX1B, 2q22

Data extracted from OMIM (http://www.ncbi.nlm.nih.gov/omim) and the reader is referred to

that sourcefor updated information as newentries areaddedand data arerevised.The reader

can alsogo directly to GeneTests (http://www.genetests.org), to whichOMIM links, for updated

information regardingthe availabilityof genetic testing on a clinical or research basis.



5/13

cephaly compared to 8.8% of the 1,159 normoce-

phalic children ( p 0.001).29

Two Class I (n 2,445) studies and one Class

III (n 540) study of children with CP found an

average incidence of congenital microcephaly of

1.8%.30-32 In 3 Class III (n 338) studies, the

combined prevalence of congenital and postnatal

onset microcephaly ranged from 32.5% to 81%

and averaged 47.9%.33-35 In one of these studies

(n 96), 68% were diagnosed with postnatal on-

set microcephaly and 13% had congenital micro-

cephaly.33 Others have shown that the yield of

determining the etiology of CP is higher when mi-

crocephaly is present.36

Conclusions. CP is a common disability in children

with microcephaly. Microcephaly, particularly of

postnatal onset and identifiable etiology, is more

common in children with CP.Recommendations.

1. Because children with microcephaly are at risk for

CP, physicians and other care providers may con-sider monitoring them for early signs so that sup-

portive treatments can be initiated (Level C).

2. Because children with CP are at risk for develop-

ing acquired microcephaly, serial HC measure-

ments should be followed (Level A).

Mental retardation. What is the prevalence of microcephaly

in different populations? Prevalence estimates of micro-

cephaly in Class III surveys of institutionalized pa-

tients vary widely from 6.5%35 to 53%.37 For

children seen in neurodevelopmental clinics, 3 Class

III studies (n

933) found an average prevalence of microcephaly (2 SD) of 24.7% (range 6% to

40.4%).38-40 Similarly, a high rate of severe (3

SD) microcephaly (20%) was found in a Class III

study of 836 children undergoing evaluation for

mental retardation.e1

A number of studies have looked at the prevalence

and significance of microcephaly in children with ap-

parently normal intelligence. One Class II study of

1,006 students in mainstream classrooms found that

1.9% had mild (2 to 3 SD) and none had

severe (3 SD) microcephaly.e2 The students

with microcephaly had a similar mean IQ to thenormocephalic group (99.5 vs 105) but had lower

mean academic achievement scores (49 vs 70). A

Class III study looking at the records of 1,775 nor-

mally intelligent adolescents followed by pediatri-

cians found 11 (0.6%) with severe microcephaly

(3 SD).e3 Among a separate sample of 106 ad-

olescents with mental retardation, the prevalence

of severe microcephaly was 11%.What is the prevalence of developmental disability in individu-

als with microcephaly? Three Class I studies based on the

National Institute of Neurological Disorders and

Stroke Collaborative Perinatal Project examined data

on microcephaly. In an early report (n 9,379), half

of the children with microcephaly (males 2.3

SD, females 2.4 SD) at 1 year of age were found

to have an IQ 80 at 4 years of age.e4 A subsequent

study (n 35,704) found congenital microcephaly

(2 SD) in 1.3% and in certain populations this

conferred a twofold risk of mental retardation at 7

years of age (15.3% vs 7%).e5 The third study (n

28,820) found that of normocephalic children, 2.6%

were mentally retarded (IQ 70) and 7.4% had bor-

derline IQ scores (71–80). Of the 114 (0.4%) chil-

dren with mild microcephaly (2 to 3 SD),

10.5% were mentally retarded and 28% had border-

line IQ scores.9 Severe microcephaly (3 SD) was

found in 41 (0.14%) children, of whom 51.2% were

mentally retarded and 17% had borderline IQ scores.

These findings have been supported by several Class

III studies.29,e6

A Class II retrospective study of 212 children

with microcephaly found a significant correlation be-tween the degree of microcephaly and the presence of

mental retardation. Among the 113 subjects with

mild microcephaly (2 to 3 SD), mental retarda-

tion was found in 11%. Mental retardation was diag-

nosed in 50% of the 99 subjects with severe

microcephaly (3 SD) and in all of those with an

HC less than 7 SD.e7

A number of Class III studies of children with

microcephaly have examined other clinical factors.

There are conflicting data as to whether proportion-

ate microcephaly (i.e., similar weight, height, and

head size percentiles) is predictive of developmental

and learning disabilities.9,e2 Other Class III studies

have shown that early medical illness or brain injury

are associated with microcephaly and mental retarda-

tion.e8 The pattern of head growth can thus be a

predictor of outcome: infants with normal birth

HCs who acquire microcephaly by 1 year of age

are likely to be severely delayed. On the other

hand, studies of children from countries with

emerging economies have shown that when micro-

cephaly and developmental delay are acquired as a

consequence of malnutrition, poverty, and lack of stimulation, there is significant potential for reha-

bilitation.e9 The findings from these and other se-

lected studies are summarized in appendix e-3.

Conclusions. Microcephaly is commonly found in

developmentally and cognitively impaired children.

Children with microcephaly are at a higher risk for

mental retardation and there is a correlation between

the degree of microcephaly and the severity of cogni-

tive impairment.

Recommendation. Because children with microceph-

aly are at risk for developmental disability, physicians



6/13

should periodically assess development and academic

achievement to determine whether further testing and

rehabilitative efforts are warranted (Level A).

Ophthalmologic and audiologic disorders. One Class I

study of 360 children with severe microcephaly (3

SD) found eye abnormalities in 6.4%,but in only 0.2%

of 3,600 age-matched normocephalic controls.e10 A re-

lated study found 145 casesof congenital eye malforma-tions in 212,479 consecutive births, but prevalences for

individual malformations could not be ascertained.e11

Microcephaly was among the associated malformations

in 56% of these children.

Appendix e-4 lists microcephaly syndromes in

which prominent ophthalmologic involvement has

been reported. A Boolean search of the Online Men-

delian Inheritance in Man (OMIM) database of the

499 genetic syndromes associated with microcephaly

found that 241 (48%) of the entries mentioned vari-

ous ophthalmologic abnormalities. This search

method provides an upper estimate of the frequency

with which ophthalmologic abnormalities might be

found in patients with syndromic microcephaly.

A study of 100 children with complex ear anomalies

reported that 85 had neurologic involvement and 13

had microcephaly.e12 There are no published studies

regarding the frequency of audiologic disorders in chil-

dren with microcephaly. Appendix e-5 lists OMIM mi-

crocephaly syndromes in which prominent audiologic

involvement has been reported. A Boolean search of

OMIM listings of genetic syndromes associated with

microcephaly found 113 (23%) in which hearing loss

had been described.

Conclusions. Ophthalmologic disorders are more

common in children with microcephaly but the fre-

quency, nature, and severity of this involvement has not

been studied. Data on the prevalence of audiologic

disorders in children with microcephaly have not

been reported.Recommendation. Screening for ophthalmologic ab-

normalities in children with microcephaly may be

considered (Level C).

Clinical context. Certain microcephaly syndromes

are classically characterized by sensory impairments,

as listed in appendices e-4 and e-5. Early identifica-

tion of visual and hearing deficits may help with both

the identification of a syndromic diagnosis and the

supportive care of the child.

CLINICAL CONTEXT: CONGENITAL AND POSTNA-

TAL ONSET MICROCEPHALY Microcephaly can be

categorized as either congenital or of postnatal onset.

Diagnostic approaches for each type, summarized in

figures 1 and 2, are general overviews of a complex eval-

uation that is beyond the scope of this parameter to

describe in further detail. Some online resources avail-

able to assist clinicians in the evaluation are described in

appendix 2.

Congenital microcephaly. Many medical experts ad-

vocate doing a prompt and comprehensive evalua-

tion of congenital microcephaly, whether mild or

Figure1 Evaluationof congenitalmicrocephaly



7/13

severe, given the risk of neurodevelopmental impair-

ment and the parental anxiety associated with the

diagnosis.2,20,21 Consultation with a neurologist and

geneticist are frequently helpful in guiding the diag-nostic evaluation and in supporting and educating

families. Establishing a more specific diagnosis pro-

vides valuable information regarding etiology, prog-

nosis, treatment, and recurrence risk.

The initial history, examination, and screening labo-

ratory testing may suggest a specific diagnosis or

diagnostic category, allowing further screening or con-

firmatory testing to be targeted, if necessary. If the ini-

tial evaluation is negative and the child appears to have

isolated microcephaly, the results of a head MRI may

help to categorize the type of microcephaly using the

criteria outlined in appendix 3. Testing for specific con-

ditions (table 1) may establish a diagnosis. In newborns

with proportionate microcephaly and an unrevealing

initial evaluation, ongoing monitoring may reveal little

neurodevelopmental impairment.

Postnatal onset microcephaly. Microcephaly from ac-

quired insults to the CNS or from progressive metabol-

ic/genetic disorders is usually apparent by age 2 years.

Mild or proportionate microcephaly may go unrecog-

nized unless a child’s HC is measured accurately. Mak-

ing comparisons to parents’ HCs may be important as

familial forms of mild microcephaly, some associated

with specific genetic disorders, have been described.

The complex issues influencing the appropriate timing

and extent of testing are discussed in several excellentreviews.1,2,19,e11 Currently available assessment tools

may not ultimately establish a specific etiologic diagno-

sis. As neurodevelopmental research progresses, the

need for testing children with microcephaly of undeter-

mined origin should be reassessed.

RECOMMENDATIONSFOR FUTURE RESEARCH

1. Large, prospective epidemiologic studies are needed

to establish the prevalence of congenital and postna-

tal microcephaly and the degree to which the signif-

icance of microcephaly is altered by ethnicbackground, a history of prematurity, head shape,

and parental head size. Such studies may also clarify

the significance of head size that remains within the

normal range for the average population but which

1) is 2 SD for the person’s family or 2) has de-

creased more than 2 SD over time. In addition, the

appropriate ages at and until which HC should be

measured and plotted to evaluate for patterns of ab-

normal brain growth need to be revisited.

2. Large, prospective studies of neuropsychological,

neuroimaging, genetic, metabolic, neurophysiologic

Figure2 Evaluation of postnatal onsetmicrocephaly



8/13

(i.e., EEG), and ancillary (vision and hearing) tests

should be undertaken in children with microcephaly

to establish the diagnostic yields of these tests and

inform the development of an evidence-based algo-

rithmic approach to evaluation.

3. The burden of neurodevelopmental disability and

comorbid medical illness in children with micro-

cephaly should be more thoroughly studied to

guide the provision of preventative and rehabilita-

tive services that might improve outcomes.

DISCLOSURE

Dr. Ashwal serves on the scientific advisory board of the Tuberous Sclero-

sis Association and the International Pediatric Stroke Society; serves as an

editor of Pediatric Neurology ; and receives research support from the NIH

[1 R01 NS059770-01A2 (PI), 1 R01 NS054001-01A1 (PI), and R01

CA107164-03 (PI)]. Dr. Michelson reports no disclosures. Dr. Plawner

receives royalties from publishing PEMSoft: The Pediatric Emergency Med-

icine Software (2007 and 2008); receives research support from the NIH

[NO1-HD-3-3351 (Co-investigator); and has served as an expert consul-

tant in a legal proceeding. Dr. Dobyns serves on the editorial advisory

boards of the American Journal of Medical Genetics and Clinical Dysmor-

phology and receives research support from the NIH [1R01-NS050375

(PI) and 1R01-NS058721 (PI)].

DISCLAIMER

This statement is provided as an educational service of the American

Academy of Neurology and the Child Neurology Society. It is based on an

assessment of current scientific and clinical information. It is not intended

to include all possible proper methods of care for a particular neurologic

problem or all legitimate criteria for choosing to use a specific procedure.

Neither is it intended to exclude any reasonable alternative methodolo-

gies. The AAN and the Child Neurology Society recognize that specific

patient care decisions are the prerogative of the patient and the physician

caring for the patient, based on all of the circumstances involved. The

clinical context section is made available in order to place the evidence-

based guideline(s) into perspective with current practice habits and chal-

lenges. No formal practice recommendations should be inferred.

CONFLICT OF INTEREST STATEMENT

The American Academy of Neurology is committed to producing inde-

pendent, critical, and truthful clinical practice guidelines (CPGs). Signifi-

cant efforts are made to minimize the potential for conflicts of interests to

influence the recommendation of this CPG. To the extent possible, the

AAN keeps separate those who have a financial stake in the success or

failure of the products appraised in the CPGs and the developers of the

guidelines. Conflict of interest forms were obtained from all authors and

reviewed by an oversight committee prior to project initiation. AAN lim-

its the participation of authors with substantial conflicts of interest. The

AAN forbids commerci al participa tion in, or funding of, guideline

projects. Drafts of the guidelines have been reviewed by at least three AAN

committees, a network of neurologists, Neurology ®

peer reviewers, andrepresentatives from related fields. The AAN Guideline Author Conflict

of Interest Policy can be viewed at http://www.aan.com.

APPENDIX 1A

Quality Standards Subcommittee Members 2007–2009: Jacqueline French,

MD, FAAN (Chair); Charles E. Argoff, MD; Eric Ashman, MD; Stephen

Ashwal, MD, FAAN (Ex-Officio); Christopher Bever, Jr., MD, MBA,

FAAN; John D. England, MD, FAAN; Gary M. Franklin, MD, MPH,

FAAN (Ex-Officio); Deborah Hirtz, MD, FAAN (Ex-Officio); Robert G.

Holloway, MD, MPH, FAAN; Donald J. Iverson, MD, FAAN; Steven R.

Messé, MD; Leslie A. Morrison, MD; Pushpa Narayanaswami, MD,

MBBS; James C. Stevens, MD, FAAN (Ex-Officio); David J. Thurman,

MD, MPH (Ex-Officio); Dean M. Wingerchuk, MD, MSc, FRCP(C);

Theresa A. Zesiewicz, MD, FAAN.

APPENDIX 1B

Child Neurology Society Practice Committee Members: Bruce Cohen, MD

(Chair); Diane Donley, MD; Bhuwan Garg, MD; Michael Goldstein

(Emeritus); Brian Grabert, MD; David Griesemer, MD; Edward Kovnar,

MD; Agustin Legido, MD; Leslie Morrison, MD; Ben Renfroe, MD;

Shlomo Shinnar, MD; Russell Snyder, MD; Carmela Tardo, MD; Greg

Yim, MD.

APPENDIX 2

Resources for evaluating children with microcephaly

1. Accurate head circumference (HC) measurement is obtained with a flexible non-stretchable measuring tape pulled tightly across the most

prominent part on the back (occiput) and front (supraorbital ridges) of

the head.

Standardized growth charts in percentiles for boys and girls from birth

to age 36 months are available online from the Web site of the National

Center for Health Statistics.

Growth charts for HC for boys and girls from birth to age 5 years and

plotted as standard deviations from the mean are available through the

World Health Organization Web site. These charts, updated in 2006,

are based on data from 8,500 well-nourished children from Brazil,

Ghana, India, Norway, Oman, and the United States.

Measurements from patients older than 36 months can be evaluated

using charts derived in 1968 from pooled data from a few countries(Nellhaus G. Head circumference from birth to eighteen years: com-

posite international and interracial graphs. Pediatrics 1968;41:106–

110), made available online through the Web site of the Department of

Neurology at Emory University.

Growth charts for premature infants and for children born in countries

other than the United States, including China, India, Korea, and Viet-

nam, can be found online at Web sites specializing in information for

prospective adoptive parents, such as that of the Center for Adoption

Medicine. There is evidence that extremely premature infants (1 kg)

who survive never catch up to infants with birth weights over 1 kg. In

these cases, if one uses standard HC graphs, many normal children will

appear microcephalic and might be subjected to unnecessary evalua-

tions. (Sheth RD, Mullett MD, Bodensteiner JB, Hobbs GR. Longitu-

dinal head growth in developmentally normal preterm infants. ArchPediatr Adolesc Med 1995;149:1358–1361.)

Web sites:

http://www.cdc.gov/growthcharts

http://www.who.int/childgrowth/standards/hc_for_age/en/index.html

http://www.pediatrics.emory.edu/divisions/neurology/hc.pdf

http://www.adoptmed.org/topics/growth-charts.html

2. The freely searchable Online Mendelian Inheritance in Man (OMIM)

database contains close to 500 entries for genetic disorders associated

with microcephaly.

Web site: http:// www.ncbi.nlm.nih.gov/omim

3. GeneTests is a publicly funded medical genetics information resource

that provides reviews of genetic disorders causing microcephaly and a

directory of laboratories that perform confirmatory genetic and enzy-matic testing.

Web site: http:// www.genetests.org

4. Pictures of Standard Syndromes and Undiagnosed Malformations

(POSSUM) is a computer-based system that can be purchased for

approximately $1,000. It contains information on more than 3,000

syndromes, including chromosomal and metabolic disorders associated

with multiple malformations and skeletal dysplasias.

Web site: http:// www.possum.net.au

5. The London Dysmorphology Database, London Neurogenetics Data-

base, and Dysmorphology Photo Library on CD-ROM (2001, 3rd

edition) combine 2 comprehensive databases and an extensive photo

library onto a single CD-ROM that can be purchased for $2,495.



9/13

There are more than 3,400 nonchromosomal syndromes in the dys-

morphology database and nearly 3,300 neurologic disorders in the

neurogenetics database, with online updates made available to regis-

tered users.

Web site: http://www. lmdatabases.com

APPENDIX 3

MRI-based classification of microcephaly*

1. Microcephaly with normal to thin cortex

a. Autosomal recessive microcephaly i. Autosomal recessive microcephaly with normal or slightly

short stature and high function

(a) MCPH1 mutations

(b) ASPM mutations

(c) CDK5RAP2 mutations

(d) CENPJ mutations

ii. Autosomal recessive microcephaly with normal or minor short

stature and very poor function

(a) Profound microcephaly—Amish-type lethal microcephaly

(SLC25A19 mutations)

(b) Less severe microcephaly with periventricular nodular het-

erotopia ( ARFGEF2 mutations)

(c) Less severe microcephaly with abnormal frontal cortex

and thin corpus callosum—Warburg micro syndrome

(RAB3GAP mutations)b. Extreme microcephaly with simplified gyral pattern and normal

stature

i. Extreme microcephaly with jejunal atresia

ii. Microcephaly with pontocerebellar hypoplasia

c. Primary microcephaly, not otherwise classified

2. Microlissencephaly (extreme microcephaly with thick cortex)

a. MLIS with thick cortex (Norman-Roberts syndrome)

b. MLIS with thick cortex, severe brainstem and cerebellar hypopla-

sia (Barth MLIS syndrome)

c. MLIS with severe, proportional short stature—Seckel syndrome

( ATR mutation)

d. MLIS with mildly to moderately thick (6-mm to 8-mm) cortex,

callosal agenesis

3. Microcephaly with polymicrogyria or other cortical dysplasias

a. Extreme microcephaly with diffuse or asymmetric polymicrogyria

b. Extreme microcephaly with ACC and cortical dysplasia

*Adapted from Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R,

Dobyns WB. A developmental and genetic classification for malforma-

tions of cortical development. Neurology 2005;65:1873–1887.

The reader can also go directly to GeneTests (http://www.genetests.

org), to which OMIM links, for updated information regarding the availabil-

ity of genetic testing on a clinical or research basis.

APPENDIX 4

Syndromic classification of primary microcephaly and

associated genes*

Autosomal recessive microcephaly (OMIM 251200) MCPH1 (Microcephalin; 8p22-pter)

MCPH2 (19q13.1-13.2)

MCPH3 (CDK5RAP2; 9q34)

MCPH4 (15q15-q21)

MCPH5 (ASPM; 1q31 )

MCPH6 (CENPJ; 13q12.2 )

Microcephaly with severe IUGR

ATR Seckel syndrome

PCNT2 microcephalic osteodysplastic primordial dwarfism, type

2; Seckel syndrome

Microcephaly with a simplified gyral pattern (OMIM 603802)

Autosomal dominant microcephaly (OMIM 156580)

Amish lethal microcephaly (OMIM 607196)

Other genes

AKT3 severe postnatal microcephaly

SLC25A19 Amish lethal microcephaly

LIS1 lissencephaly

DCX lissencephaly (X-linked)

SHH holoprosencephaly

ZIC2 holoprosencephaly

TGIF holoprosencephaly

SIX3 holoprosencephaly

DHCR7 Smith-Lemli-Opitz syndrome

CREBBP Rubinstein-Taybi syndrome

PAK3 X-linked mental retardation

NBS1 Nijmegen breakage syndrome MECP2 Rett syndrome (X-linked)

*Inheritance is autosomal recessive excepted where noted. Data collated

from Mochida and Walsh20; Alderton GK, Galbiati L, Griffith E, et al.

Regulation of mitotic entry by microcephalin and its overlap with ATR

signaling. Nat Cell Biol 2006;8:725–733; Bond J, Woods CG. Cytoskel-

etal genes regulating brain size. Curr Opin Cell Biol 2006;18:95–101;

Woods CG, Bond J, Enard W. Autosomal recessive primary microcephaly

(MCPH): a review of clinical, molecular, and evolutionary findings. Am J

Hum Genet 2005;76:717–728.

The reader can also go directly to GeneTests (http://www.genetests.

org), to which OMIM links, for updated information regarding the avail-

ability of genetic testing on a clinical or research basis.

Received December 18, 2008. Accepted in final form July 7, 2009.

REFERENCES

1. Leviton A, Holmes LB, Allred EN, Vargas J. Method-

ologic issues in epidemiologic studies of congenital micro-

cephaly. Early Hum Dev 2002;69:91–105.

2. Opitz JM, Holt MC. Microcephaly: general considerations

and aids to nosology. J Craniofac Genet Dev Biol 1990;10:

75–204.

3. Roche AF, Mukherjee D, Guo SM, Moore WM. Head

circumference reference data: birth to 18 years. Pediatrics

1987;79:706–712.

4. Barkovich AJ, Ferriero DM, Barr RM, et al. Microlissen-

cephaly: a heterogeneous malformation of cortical devel-

opment. Neuropediatrics 1999;29:113–119.5. Dobyns WB, Andermann E, Andermann F, et al. X-linked

malformations of neuronal migration. Neurology 1996;

47:331–339.

6. Woods CG. Human microcephaly. Curr Opin Neurobiol

2004;14:112–117.

7. Jackson AP, Eastwood H, Bell SM, et al. Identification of

microcephalin, a protein implicated in determining the size of

the human brain. Am J Hum Genet 2002;71:136–142.

8. Vargas JE, Allred EN, Leviton A, Holmes LB. Congenital

microcephaly: phenotypic features in a consecutive sample

of newborn infants. J Pediatr 2001;139:210–214.

9. Dolk H. The predictive value of microcephaly during the

first year of life for mental retardation at seven years. Dev Med Child Neurol 1991;33:974–983.

10. Jaworski M, Hersh JH, Donat J, Shearer LT, Weisskopf B.

Computed tomography of the head in the evaluation of

microcephaly. Pediatrics 1986;78:1064–1069.

11. Ito M, Okuno T, Mikawa H. Computed tomographic

study of children with microcephaly. No To Hattatsu

1989;21:440–444.

12. Steinlin M, Zurrer M, Martin E, Boesch CH, Largo RH,

Bottshauser E. Contribution of MRI in the evaluation of

microcephaly. Neuropediatrics 1991;22:184–189.

13. Sugimoto T, Yasuhara A, Nishida N, Murakami K, Woo

M, Kobayashi Y. MRI of the head in the evaluation of

microcephaly. Neuropediatrics 1993;24:4–7.



10/13

14. Pandey A, Phadke SR, Gupta N, Phadke RV. Neuroimaging

in mental retardation. Indian J Pediatr 2004;71:203–209.

15. Custer DA, Vezina LG, Vaught DR, et al. Neurodevelop-

mental and neuroimaging correlates in nonsyndromal mi-

crocephalic children. J Dev Behav Pediatr 2000;21:12–18.

16. Wycliffe ND, Thompson JR, Holshouser BA, Ashwal S. Pe-

diatric neuroimaging. In: Swaiman KF, Ashwal S, Ferriero

DM. Pediatric Neurology Principles & Practice, Fourth edi-

tion. Philadelphia: Mosby Elsevier; 2006:167–202.

17. Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R,

Dobyns WB. A developmental and genetic classificationfor malformations of cortical development. Neurology

2005;65:1873–1887.

18. Lalaguna-Mallada P, Alonso-del Val B, Abió-Albero S,

Peña-Segura JL, Rebage V, López-Pisón J. Microcephalus

as the reason for visiting a regional referral neuropaediatric

service. Rev Neurol 2004;38:106–110.

19. den Hollander NS, Wessels MW, Los FJ, Ursem NT,

Niermeijer MF, Wladimiroff JW. Congenital micro-

cephaly detected by prenatal ultrasound: genetic aspects

and clinical significance. Ultrasound Obstet Gynecol

2000;15:282–287.

20. Mochida GH, Walsh CA. Molecular genetics of human

microcephaly. Curr Opin Neurol 2001;14:151–156.

21. Abuelo D. Microcephaly syndromes. Semin Pediatr Neu-

rol 2007;14:118–127.

22. Kelley RI, Robinson D, Puffenberger EG, Strauss KA, Mor-

ton DH. Amish lethal microcephaly: a new metabolic disor-

der with severe congenital microcephaly and 2-ketoglutaric

aciduria. Am J Med Genet 2002;112:318–326.

23. Shevell M, Ashwal S, Donley D, et al. Practice parameter:

evaluation of the child with global developmental delay:

report of the Quality Standards Subcommittee of the

American Academy of Neurology and The Practice Com-

mittee of the Child Neurology Society. Neurology 2003;

60:367–380.

24. Abdel-Salam GM, Halasz AA, Czeizel AE. Association of

epilepsy with different groups of microcephaly. Dev MedChild Neurol 2000;42:760–767.

25. Qazi QH, Reed TE. A problem in diagnosis of primary

versus secondary microcephaly. Clin Genet 1973;4:46–

52.

26. Berg AT, Levy SR, Novotny EJ, Shinnar S. Predictors of

intractable epilepsy in childhood: a case-control study.

Epilepsia 1996;37:24–30.

27. Chawla S, Aneja S, Kashyap R, Mallika V. Etiology and

clinical predictors of intractable epilepsy. Pediatr Neurol

2002;27:186–191.

28. Aneja S, Ahuja B, Taluja V, Bhatia VK. Epilepsy in children

with cerebral palsy. Indian J Pediatr 2001;68:111–115.

29. Watemberg N, Silver S, Harel S, Lerman-Sagie T. Signifi-

cance of microcephaly among children with developmental

disabilities. J Child Neurol 2002;17:117–122.30. Croen LA, Grether JK, Curry CJ, Nelson KB. Congenital

abnormalities among children with cerebral palsy: more

evidence for prenatal antecedents. J Pediatr 2001;138:

804–810.

31. Pharoah PO. Prevalence and pathogenesis of congenital

anomalies in cerebral palsy. Arch Dis Child Fetal Neonatal

Ed 2007;92:F489–443.

32. Laisram N, Srivastava VK, Srivastava RK. Cerebral palsy:

an etiological study. Indian J Pediatr 1992;59:723–728.

33. Edebol-Tysk K. Epidemiology of spastic tetraplegic cere-

bral palsy in Sweden: I: impairments and disabilities. Neu-

ropediatrics 1989;20:41–45.

34. Lubis MU, Tjipta GD, Marbun MD, Saing B. Cerebral

palsy. Paediatr Indones 1990;30:65–70.

35. Suzuki J, Ito M, Tomiwa K, Okuno T. A clinical study of

cerebral palsy in Shiga; 1977–1986: II: severity of the dis-

ability and complications in various types of cerebral palsy.

No To Hattatsu 1999;31:336–342.

36. Shevell MI, Majnemer A, Morin I. Etiologic yield of cere-

bral palsy: a contemporary case series. Pediatr Neurol

2003;28:352–359.

37. Roboz P. Microcephaly. Aust J Ment Retard 1973;2:173–

179.

38. Smith RD. Abnormal head circumference in learning-

disabled children. Dev Med Child Neurol 1981;23:626–

632.

39. Martin HP. Microcephaly and mental retardation. Am JDis Child 1970;119:128–131.

40. Desch LW, Anderson SK, Snow JH. Relationship of head

circumference to measures of school performance. Clin Pe-

diatr 1990;29:389–392.



11/13

Editor’s Note to Authors and Readers: Levels of Evidence in Neurology ®

Effective January 15, 2009, authors sub-

mitting Articles or Clinical/Scientific

Notes to Neurology ® that report on clin-

ical therapeutic studies must state the

study type, the primary research ques-tion(s), and the classification of level of

evidence assigned to each question based

on the classification scheme require-

ments shown (top). While the authors

will initially assign a level of evidence,

the final level will be adjudicated by an

independent team prior to publication.

Ultimately, these levels can be translated

into classes of recommendations for clin-

ical care, as shown (bottom). For more

information, please access the articles

and the editorial on the use of classifica-tion of levels of evidence published in

Neurology .1-3

1. French J, Gronseth G. Lost in a jungle of evi-dence: we need a compass. Neurology 2008;71:1634–1638.

2. Gronseth G, French J. Practice parameters andtechnology assessments: what they are, whatthey are not, and why you should care. Neurol-ogy 2008;71:1639–1643.

3. Gross RA, Johnston KC. Levels of evidence:taking Neurology ® to the next level. Neurology 2008;72:8–10.



12/13

DOI 10.1212/WNL.0b013e3181b783f72009;73;887-897 Neurology

Stephen Ashwal, David Michelson, Lauren Plawner, et al.Neurology and the Practice Committee of the Child Neurology Society

review): Report of the Quality Standards Subcommittee of the American Academy ofPractice Parameter: Evaluation of the child with microcephaly (an evidence-based

This information is current as of September 14, 2009

Online ISSN: 1526-632X.1951, it is now a weekly with 48 issues per year. Copyright . All rights reserved. Print ISSN: 0028-3878.

® is the official journal of the American Academy of Neurology. Published continuously since Neurology


13/13

ServicesUpdated Information &

http://www.neurology.org/content/73/11/887.full.htmlincluding high resolution figures, can be found at:

Supplementary Material

mlhttp://www.neurology.org/content/suppl/2009/09/13/73.11.887.DC2.ht

mlhttp://www.neurology.org/content/suppl/2009/09/13/73.11.887.DC1.ht

mlhttp://www.neurology.org/content/suppl/2010/09/12/73.11.887.DC3.htSupplementary material can be found at:

References http://www.neurology.org/content/73/11/887.full.html##ref-list-1

This article cites 39 articles, 8 of which you can access for free at:

Citations http://www.neurology.org/content/73/11/887.full.html##otherarticles

This article has been cited by 7 HighWire-hosted articles:

Subspecialty Collections

http://www.neurology.org//cgi/collection/mental_retardationMental retardation

http://www.neurology.org//cgi/collection/developmental_disordersDevelopmental disorders

http://www.neurology.org//cgi/collection/all_geneticsAll Geneticsfollowing collection(s):This article, along with others on similar topics, appears in the

Permissions & Licensing

http://www.neurology.org/misc/about.xhtml#permissionsits entirety can be found online at:Information about reproducing this article in parts (figures,tables) or in

Reprints

http://www.neurology.org/misc/addir.xhtml#reprintsusInformation about ordering reprints can be found online:

Online ISSN: 1526-632X.1951, it is now a weekly with 48 issues per year. Copyright . All rights reserved. Print ISSN: 0028-3878.

® is the official journal of the American Academy of Neurology. Published continuously since Neurology
http://www.neurology.org/content/73/11/887.full.htmlhttp://www.neurology.org/content/73/11/887.full.htmlhttp://www.neurology.org/content/73/11/887.full.htmlhttp://www.neurology.org/content/suppl/2009/09/13/73.11.887.DC2.htmlhttp://www.neurology.org/content/suppl/2009/09/13/73.11.887.DC2.htmlhttp://www.neurology.org/content/suppl/2009/09/13/73.11.887.DC2.htmlhttp://www.neurology.org/content/suppl/2009/09/13/73.11.887.DC2.htmlhttp://www.neurology.org/content/suppl/2009/09/13/73.11.887.DC2.htmlhttp://www.neurology.org/content/suppl/2009/09/13/73.11.887.DC1.htmlhttp://www.neurology.org/content/suppl/2009/09/13/73.11.887.DC1.htmlhttp://www.neurology.org/content/suppl/2009/09/13/73.11.887.DC1.htmlhttp://www.neurology.org/content/suppl/2010/09/12/73.11.887.DC3.htmlhttp://www.neurology.org/content/suppl/2010/09/12/73.11.887.DC3.htmlhttp://www.neurology.org/content/73/11/887.full.html##ref-list-1http://www.neurology.org/content/73/11/887.full.html##ref-list-1http://www.neurology.org/content/73/11/887.full.html##ref-list-1http://www.neurology.org/content/73/11/887.full.html##otherarticleshttp://www.neurology.org/content/73/11/887.full.html##otherarticleshttp://www.neurology.org/content/73/11/887.full.html##otherarticleshttp://www.neurology.org//cgi/collection/mental_retardationhttp://www.neurology.org//cgi/collection/mental_retardationhttp://www.neurology.org//cgi/collection/developmental_disordershttp://www.neurology.org//cgi/collection/developmental_disordershttp://www.neurology.org//cgi/collection/all_geneticshttp://www.neurology.org//cgi/collection/all_geneticshttp://www.neurology.org/misc/about.xhtml#permissionshttp://www.neurology.org/misc/about.xhtml#permissionshttp://www.neurology.org/misc/about.xhtml#permissionshttp://www.neurology.org/misc/addir.xhtml#reprintsushttp://www.neurology.org/misc/addir.xhtml#reprintsushttp://www.neurology.org/misc/addir.xhtml#reprintsushttp://www.neurology.org/misc/addir.xhtml#reprintsushttp://www.neurology.org/misc/about.xhtml#permissionshttp://www.neurology.org//cgi/collection/mental_retardationhttp://www.neurology.org//cgi/collection/developmental_disordershttp://www.neurology.org//cgi/collection/all_geneticshttp://www.neurology.org/content/73/11/887.full.html##otherarticleshttp://www.neurology.org/content/73/11/887.full.html##ref-list-1http://www.neurology.org/content/suppl/2009/09/13/73.11.887.DC2.htmlhttp://www.neurology.org/content/suppl/2009/09/13/73.11.887.DC2.htmlhttp://www.neurology.org/content/suppl/2009/09/13/73.11.887.DC1.htmlhttp://www.neurology.org/content/suppl/2009/09/13/73.11.887.DC1.htmlhttp://www.neurology.org/content/suppl/2010/09/12/73.11.887.DC3.htmlhttp://www.neurology.org/content/suppl/2010/09/12/73.11.887.DC3.htmlhttp://www.neurology.org/content/73/11/887.full.html

practice parameter: evaluation of the child with microcephaly (an evidence-based review)

Documents